Blockade of CaV3 calcium channels and induction of G0/G1 cell cycle arrest in colon cancer cells by gossypol

棉酚 内质网 细胞生长 电压依赖性钙通道 膜片钳 细胞凋亡 细胞周期 化学 生物 分子生物学 内科学 细胞生物学 生物化学 医学 受体
作者
Osbaldo López-Charcas,Oumnia Benouna,Roxane Lemoine,Margarita Jacaranda Rosendo‐Pineda,Tonantzin Guadalupe Anguheven‐Ledezma,Lizeth Sandoval‐Vazquez,Martin Leonardo Gallegos‐Gomez,Leticia Robles-Martínez,Zazil Herrera‐Carrillo,Miguel Ramírez‐Aragón,Ana Alfaro,Stéphanie Chadet,Fabio Ferro,Pierre Besson,Lin‐Hua Jiang,Sadanandan E. Velu,Agustín Guerrero‐Hernández,Sébastien Roger,Juan Carlos Gómora
出处
期刊:British Journal of Pharmacology [Wiley]
卷期号:181 (22): 4546-4570
标识
DOI:10.1111/bph.16497
摘要

Abstract Background and Purpose Gastrointestinal tumours overexpress voltage‐gated calcium (Ca V 3) channels (Ca V 3.1, 3.2 and 3.3). Ca V 3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti‐tumour properties and inhibits Ca V 3 currents. A systematic study was performed on gossypol blocking mechanism on Ca V 3 channels and its potential anticancer effects in colon cancer cells, which express Ca V 3 isoforms. Experimental Approach Transcripts for Ca V 3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on Ca V 3 channels was investigated by combining heterologous expression systems and patch‐clamp experiments. The anti‐tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca 2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca 2+ indicators. Key Results High levels of Ca V 3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of Ca V 3 isoforms is concentration‐ and use‐dependent interacting with the closed, activated and inactivated conformations of Ca V 3 channels. Gossypol and Ca V 3 channels down‐regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G 0 /G 1 and G 2 /M phases, respectively. Ca V 3 channels underlie the vectorial Ca 2+ uptake by endoplasmic reticulum in colorectal cancer cells. Conclusion and Implications Gossypol differentially blocked Ca V 3 channel and its anticancer activity was correlated with high levels of Ca V 3.1 and Ca V 3.2 in colorectal cancer cells. The Ca V 3 regulates cell proliferation and Ca 2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.

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